1. Field of the Invention
The present invention relates to certain sufonamide derivatives that inhibit procollagen C-proteinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.
2. Background Information and Related Disclosures
The collagens are integral components of connective tissue. At present nineteen types of collagens have been identified. The interstitial collagen types I, II, and III are the major collagen components of tissue. These collagens are synthesized as procollagen precursor molecules having amino- and carboxy-terminal peptide extensions also known as pro-regions. These pro-regions are typically cleaved upon secretion of the procollagen molecule to give a mature collagen molecule which is capable of association into highly structured collagen fibers, ((see, e.g., Fessler and Fessler, Annu. Rev. Biochem. 47, 129, (1978); Kivirikko et al., Extracellular Matrix Biochemistry (1984) and Kuhn, Structure and Function of Collagen Types (eds. Mayne, R and Burgeson, R. E.), Academic Press, Inc., Orlando, Fla., pp. 1-42 (1987)). It is well established that excessive collagen deposition is associated with a variety of fibrotic diseases such as interstitial pulmonary fibrosis, pericentral fibrosis, Symmers"" fibrosis, perimuscular fibrosis, kidney fibrosis, endocardial sclerosis, hepatitis, acute respiratory distress syndrome, arthritis, cystic fibrosis, tendon surgery, corneal scarring, surgical adhesions, scleroderma, chronic allograft rejection, hemodialysis shunt fibrosis, liver fibrosis and restenosis. These diseases are characterized by excessive deposits of fibrillar interstitial collagens that are resistant to proteolytic degradation thus leading to the symptoms of fibrosis. Therefore, inhibition of the pathological deposition of these collagens should help in the treatment of these diseases.
Recent studies suggest that C-proteinase is the essential enzyme that catalyzes the cleavage of the C-propeptide of types I, II, and III collagens and is therefore instrumental in the formation of functional collagen fibers ((see, Fertala et al., J. Biol. Chem., 269, 11584, (1994)). It would therefore be desirable to provide procollagen C-proteinase inhibitors and thereby provide a means of combating diseases mediated by excessive deposition of these collagens. The compounds of this invention fulfill this and related needs.
In a first aspect, this invention provides sulfonamide derivatives selected from the group of compounds represented by Formula (I): 
wherein:
Z is xe2x80x94OH, xe2x80x94NHOH, or OR12 wherein R12 is alkyl;
R1 is alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)xe2x80x94X where X is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, or heteroaralkyloxy), or xe2x80x94C(xe2x95x90NRxe2x80x2)NHSO2Rxe2x80x3 (where Rxe2x80x2 is hydrogen or alkyl, and Rxe2x80x3 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl);
R is xe2x80x94CH(R2)Ar1 or xe2x80x94CH(R2)CHxe2x95x90CHAr1 where R2 is hydrogen or alkyl; and Ar1 is aryl or heteroaryl;
Ar2 is either:
(i) a phenyl ring of formula (a): 
wherein:
R3 and R7 are, independently of each other, hydrogen, alkyl, alkylthio, or halo;
R4 and R6 are, independently of each other, hydrogen, alkyl, or halo;
R5 is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy, cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or xe2x80x94Y-(alkylene)-C(O)xe2x80x94Z [where Y is a bond, xe2x80x94NRaxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2), Ra is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino, monosubstituted amino, or disubstituted amino]; or
R5 together with R4 forms xe2x80x94Oxe2x80x94(CR8R9)nxe2x80x94 where n is 2 or 3 and each R8 and R9 are, independently of each other, hydrogen or alkyl; or
the carbon atoms to which R5 and R4 are attached are fused to the C2-C3 carbons of a benzofuran ring;
provided that at least two of R3, R4, R6, and R7 are not hydrogen at the same time; or
(ii) a naphthyl ring of formula (b): 
wherein:
R10 is hydrogen, alkyl, alkoxy, or halo; and
R11 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino or alkylsulfonyl provided that both R10 and R11 are not hydrogen at the same time; and
their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers.
Within the group of compounds represented by Formula (I), sulfonamide derivatives of this invention wherein Z is NHOH are represented by Formula (Ia): 
In a second aspect, this invention provides a method of treatment of a disease treatable by administration of a therapeutically effective amount of a procollagen C-proteinase inhibitor of Formula (Ib) wherein: 
wherein:
R1 is alkyl, haloalkyl, heteroalkyl, cycloalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heteroaralkenyl, heterocyclylalkyl, cycloalkylalkyl, -(alkylene)-C(O)xe2x80x94X (where X is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, hydroxy, alkoxy, cycloalkoxy, cycloalkylalkoxy, heteroalkyloxy, aralkyloxy, or heteroaralkyloxy), or xe2x80x94C(xe2x95x90NRxe2x80x2)NHSO2Rxe2x80x3 (where Rxe2x80x2 is hydrogen or alkyl, and Rxe2x80x3 is alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, or heterocyclylalkyl);
R is xe2x80x94CH(R2)Ar1 or xe2x80x94CH(R2)CHxe2x95x90CHAr1 where R2 is hydrogen or alkyl; and Ar1 is aryl or heteroaryl;
Ar2 is either:
(i) a phenyl ring of formula (a): 
wherein:
R3 and R7 are, independently of each other, hydrogen, alkyl, alkylthio, or halo;
R4 and R6 are, independently of each other, hydrogen, alkyl, or halo;
R5 is alkyl, haloalkyl, heterocyclyl, alkylthio, arylthio, aralkylthio, heteroarylthio, heteroaralkylthio, cycloalkylthio, cycloalkylalkylthio, alkoxy, aryloxy, aralkoxy, heteroaryloxy, heteroaralkyloxy, cycloalkoxy, cycloalkylalkoxy, alkyloxycarbonyl, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino, alkylsulfonyl, arylsulfonyl, aralkylsulfonyl, heteroarylsulfonyl, heteroaralkylsulfonyl, cycloalkylsulfonyl, cycloalkylalkylsulfonyl, or xe2x80x94Y-(alkylene)-C(O)xe2x80x94Z [where Y is a bond, xe2x80x94NRaxe2x80x94, xe2x80x94Oxe2x80x94, or xe2x80x94S(O)nxe2x80x94 (where n is 0 to 2), Ra is hydrogen or alkyl, and Z is alkoxy, hydroxy, amino, monosubstituted amino, or disubstituted amino]; or
R5 together with R4 forms xe2x80x94Oxe2x80x94(CR8R9)nxe2x80x94 where n is 2 or 3 and each R8 and R9 are, independently of each other, hydrogen or alkyl; or
the carbon atoms to which R5 and R4 are attached are fused to the C2-C3 carbons of a benzofuran ring; or
(ii) a naphthyl ring of formula (b): 
wherein:
R10 is hydrogen, alkyl, alkoxy, or halo; and
R11 is hydrogen, alkyl, haloalkyl, alkylthio, alkoxy, alkyloxycarbonyl, aryloxy, hydroxy, halo, cyano, carboxy, nitro, amino, monoalkylamino, dialkylamino or alkylsulfonyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers.
In a third aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (Ia) or (Ib) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a fourth aspect, this invention provides a process for preparing compounds of Formula (Ia) or (Ib).